Although androgens via the androgen receptor (AR) are the primary regulator for biological functions of the prostate, intrinsic factors such as putative prostate-specific transcription factors may play critical roles in tissue specific androgen action. Yet, molecular mechanisms by which androgens function in a tissue specific manner have not been elucidated. Prostate-specific antigen (PSA) and human glandular kallikrein (hK2) are the prostate-specific kallikreins, which are not only of clinical significance as prostate cancer markers, but also of biological importance due to protease activities. We also believe these genes can be excellent models for dissecting the potentially novel mechanisms for controlling gene expression through the interaction of androgens/AR and tissue-specific factors in prostate cells. We hypothesize that the newly identified, prostate-specific homeobox gene, Nkx3.1, coordinates the function of the AR for the expression of the prostate specific kallikreins. A number of approaches involving molecular biology, cell biology, transgenic/knockouts will be used to address how Nkx3.1 interacts with androgens/AR for prostate-specific gene expression. These studies should provide valuable insight into molecular mechanisms of tissue-specific, androgen regulation of gene expression in prostate cells.